A variety of abused substances as well as pharmacotherapeutic agents used to treat psychiatric illnesses are thought to mediate their effects through brain amines and acetylcholine. One purpose of this project has been to evaluate, with microdialysis procedures, the regional modulation of brain amine and acetylcholine function by various pharmacological agents with relevance to psychiatry. We have found that intraventricular injections of 5'7-DHT, which depleted rat brain tissue levels of serotonin (5-HT) by 50-70%, had little effect on extracellular levels as assessed with microdialysis. Extracellular levels decreased only when tissue levels had reached over 90% depletion. It appears that presynaptic compensatory changes take place in 5-HT neurons following destruction, similar to those seen in catecholamine systems. We have also found that injections of an antisense oligonucleotide aimed at position 123 of rat tryptophan hydroxylase mRNA into the dorsal and median raphe produced anxiogenic effects in rats without altering tissue or extracellular levels of 5HT as assessed with microdialysis. Systemically administered caffeine, which increased locomotor activity, had no effect on extracellular dopamine in the n. accumbens. Galanin microinjections into the medial septum inhibited scopolamine-induced acetylcholine overflow in the rat hippocampus. Such results are consistent with the concept that galanin terminals synapsing on cholinergic cell bodies of the basal forebrain may serve to inhibit the release of acetylcholine in the terminal fields of cholinergic neurons. Intraperitoneal injections of corticosterone (CORT) increased frontal cortex norepinephrine and decreased n. accumbens DA. Tolerance developed to the effects of corticosterone on norepinephrine but not DA following chronic administration. Decreases in forebrain DA function by acute and chronic CORT may be relevant for understanding behavioral depression seen following stresses which elevate CORT.